Stem Cells, But Which Flavor?

How to recognise the cells going into a cell therapy.

Posted Feb 01, 2020 | Reviewed by Kaja Perina

Whenever I discuss stem cell therapies with non-biologist friends, I’m struck by how confused they often are about what stem cells actually are and what they do. There is particular confusion in regard to the different varieties of stem cell that are turning up in cell therapies. This is important.  There are enormous differences between the cells that compose some of the unlicensed therapies being marketed on the web, and those going through clinical trials for disorders such as Parkinson’s disease and macular degeneration. Unless we know what each does, how can we accurately judge any particular cell therapy? The first barrier to understanding is nomenclature. There are MSCs, NSCs, hESCs, iPSCs.  How to make sense of this alphabet spaghetti? 

Let’s start with adult stem cells. These are the cells found in adult animals (including humans).  Their task is to keep tissues and organs stocked with cells.  Biologists consider these stem cells to have two seminal properties: they are multipotential and self-replicative, but what do these terms mean, and why are they important? 

Consider the example of the blood stem cells found in the bone marrow.  They are multipotential, meaning that they generate all the different cell types that make up blood: red cells, lymphocytes, macrophages, etc. And they are self-replicative: they make more cells like themselves.  These are considered seminal properties because without them, the cells cannot do their job of maintaining tissue integrity.  Multipotentiality matters because the body clearly needs all blood cell types all of the time, and stem cells constitute the mechanism that evolved to achieve this. Second, because that need exists for the entire lifetime of the individual, the stem cells themselves need to be replenished, hence self-replication. Several tissues in the body depend on stem cells for their homeostasis in this way, to maintain their cell components as they age or are used up.  These are true stem cells. They are also the first stem cells to find their way into the clinic, and blood stem cells have been used for decades now in the treatment of blood disorders.  

Jack Price
multipotentiality and self-replication of neural stem cells
Source: Jack Price

Adult stem cells are defined in terms of the cell types to which they give rise: so blood stem cells generate blood, and nothing else as far as we are aware.  MSCs (mesodermal stem cells) are defined by their ability to make a range of tissue cell types (fat cells, fibroblasts, cartilage); neural stem cells make brain cells.  

So far so good, but two complications immediately arise. First, stem cells often occur in multiple locations.  MSCs, for example, turn up in the bone marrow (alongside the blood stem cells), fat tissue, and dental pulp among other places. These are all MSCs, but are they all the same? Almost certainly not. Second, adult stem cells have baby precursors and they also turn up in clinical applications. Umbilical cord stem cells, for example, are young blood stem cells. Neural stem cells can be found in adults, but also the fetal brain.  Are these less developed stem cells equivalent to the adult versions? Again, almost certainly not, but the differences, particularly in their clinical efficacy, are not always well understood.

Up until roughly a decade ago, these were the only stem cells available to clinical developers, and even now most cell therapies in the clinic—licensed or unlicensed—are these adult stem cells, from the patient or a donor, processed or au naturel. 

But now we need to make a big jump to pluripotent stem cells.  ‘Pluripotent’ means that these stem cells can make all the different cell types in the body.  So whereas the multipotent stem cells can generate a subset of cells belonging to a particular tissue (all the blood cells, for example), pluripotent cells can make all the cell types belonging to any tissue.  So, they are considerably more powerful in developmental terms.  But note: Whereas the adult stem cells exist naturally, and are extracted from tissue, the pluripotent cells are entirely artificial.  They are created by scientists in the laboratory, and correspond to nothing in the adult body.  Pluripotency does exist during development but only as a tiny cluster of cells at the earliest stage of development, and these pluripotent cells are ephemeral: after just a few days, their pluripotency is lost, never to re-emerge during the lifetime of the individual.

There are essentially two types of pluripotent stem cells available to researchers. Embryonic stem cells (ES cells) are made from precisely that ephemeral population of embryonic cells found in the human embryo.  Researchers have worked out how to take that tiny cluster and expand them into a permanent cell line, from which any number of other derivatives can be created.

The second type are called induced pluripotent stem cells (iPS cells). They are generated by an even more unlikely route. If any cell taken from the adult body is forced to express a combination of four genes—genes it wouldn’t normally express —then quite remarkably this turns the cell into a pluripotent stem cell, essentially identical to the ES cells made from true embryonic tissue.  And again, such iPS cells can be expanded indefinitely.  There are now hundreds of both types of cell lines available across laboratories worldwide: a remarkable achievement for stem cell science over the last decade or two.

So here is the strange thing: You might imagine that being ‘natural’, the adult cells would be the better bet as the starting point from which to make a cell therapy. After all, who wants to be injected with a totally artificial cell type?  But you’d be wrong.  The most promising new cell therapies are being generated from pluripotent cells.  Why?—because the pluripotent cells have three properties the adult cells don’t have.

First is the property we have already met: pluripotency.  ES and iPS cells can make anything. All that is required is the ingenuity of researchers to devise the right protocol for a particular cell type, and unlimited numbers of that cell type can be manufactured. Cells that would otherwise be unreachable from either patients or donors—cells from the eye, or the brain, or the heart—can simply be made in a dish. 

Second, these derivatives can be made in unimaginably large numbers.  They are, to use the jargon, ‘scalable’.  A problem with the adult cells has always been that once you have isolated them (from the bone marrow, for example), they are frequently hard to grow.  And even if you can get them to expand, they often change their properties during the process, so what you end up with is not what you started with, and often not what you want. The pluripotency and scalability of pluripotent cells lends itself to consistent manufacture in a manner that has been hard to achieve with most adult stem cell populations.

The third property is the most intriguing.  Pluripotent cells can actually build tissue from scratch.  Consider neural stem cells, taken either from the adult brain or from a fetus.  They are multipotential, which in this context means that they can generate a range of nerve cells.  Nonetheless, they cannot build brain tissue.  The nerve cells they generate will never be more than a scramble of ill-assorted, disorganised components.  All the cell types may be there, but like the pieces of a jigsaw puzzle tipped out onto the table, they don’t form a picture.  

Contrast this with what happens when you differentiate pluripotent cells into brain tissue.  As they differentiate, they start to mimic precisely what would happen in the embryo.  They begin to build a piece of brain, and just as during normal brain development the different brain cell types are generated in a specific sequence and slotted into the new structure in a specific order, so the differentiating neural cells start to build brain, step by step.  They don’t just make the pieces of the jigsaw: they put the jigsaw together and make the complete picture.

Pluripotent cells have opened previously unattainable opportunities, in regenerative medicine certainly, but also in disease modelling, and perhaps the most exciting of all—organoids—a topic to which I will return. So, when you are looking at stem cells, always remember to read what it says on the bottle.